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J. Biol. Chem., Vol. 279, Issue 40, 42270-42278, October 1, 2004

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Morphological Adjustment of Senescent Cells by Modulating Caveolin-1 Status^*

Kyung A Cho, Sung Jin Ryu, Yoon Sin Oh, Ji Hyeun Park, Jung Weon Lee, Hwang-Phill Kim, Kyung Tae Kim, Ik Soon Jang, and Sang Chul Park¶

From the Department of Biochemistry and Molecular Biology, Aging and Apoptosis Research Center, and the Cancer Research Institute, Seoul National University College of Medicine, Seoul 110-799, Korea

Morphological change is one of the cardinal features of the senescent phenotype; for example, senescent human diploid cells have a flat large shape. However, the mechanisms underlying such senescence-related morphological alterations have not been well studied. To investigate this situation, we characterized the senescence-dependent changes of cellular structural determinants in terms of their levels and activities. These determinants included integrins, focal adhesion complexes, and small Rho GTPases, and special emphasis was placed on their relationships with caveolin-1 status. We observed that the expression integrin ₁ and focal adhesion kinase (FAK) were increased and that the phosphorylations of FAK and paxillin, hallmarks of focal adhesion formation, were also increased in senescent human diploid fibroblast cells. Moreover, the Rho GTPases Rac1 and Cdc42 were found to be highly activated in senescent cells. In addition, focal adhesion complexes and Rho GTPases were up-regulated in the caveolin-rich membrane domain in the senescent cells. Activated Rac1 and Cdc42 directly interacted with caveolin-1 in senescent cells. Interestingly, caveolin-1 knock-out senescent cells, achieved by using small interfering RNA and antisense oligonucleotide, showed disrupted focal adhesion formation and actin stress fibers via the inactivation of FAK, which resulted in morphological adjustment to the young cell-like small spindle shape. Based on the results obtained, we propose that caveolin-1 plays an important role in senescence-associated morphological changes by regulating focal adhesion kinase activity and actin stress fiber formation in the senescent cells.

Received for publication, March 2, 2004 , and in revised form, June 30, 2004.

^* This work was supported by Grant R11-2002-001-01-001 from the Aging and Apoptosis Research Center of the Korea Science and Engineering Foundation and by grants from the Korea Research Foundation for Health Science and the Ministry of Education (SNU BK21 program). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

^¶ To whom correspondence should be addressed: Dept. of Biochemistry and Molecular Biology, Aging and Apoptosis Research Center, Seoul National University College of Medicine, 28 Yungon Dong, Chong No Ku, Seoul 110-799, South Korea. Tel.: 82-2-740-8244; Fax: 82-2-744-4534; E-mail: scpark{at}snu.ac.kr.

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